The Biomarker Core will play a key role in the proposed Yale ADRC by managing the Biospecimen Repository consisting of both standard and novel biospecimens, and through the development and application of cutting-edge proteomic and epigenetic assays and bioinformatics approaches to integrate high-dimensional multi-omics data. Methods and biospecimens under the jurisdiction of the Yale ADRC Biomarker Core will facilitate the development and validation of promising biomarkers of Alzheimer?s disease (AD) susceptibility, improve AD risk prediction, and identify promising directions for development of targeted interventions. The Biomarker Core will work closely with the Data Management and Statistics Core (DMSC) in the management of the Biospecimens Repository. We will also facilitate the integration of multi-omics data with data generated by the Clinical and Imaging Cores to assess and validate both standard and novel biomarkers aimed at capturing AD heterogeneity, susceptibility, and progression. We will work with the DMSC to utilize statistical modeling of cognitive trajectories and decline, and/or considerations of mortality selection or other biases when evaluating the reliability, validity, and generalizability of AD-related biomarkers. Finally, we will work with the Education Component and Outreach Core to facilitate training and outreach in AD Biomarker acquisition and use. Specific Aims include: Aim 1: Manage Yale ADRC Biospecimen Repository. Working closely with the Clinical, Neuropathology, and DMS Cores, and NCRAD, we will manage the Yale ADRC biorepository and provide biospecimens to ADRC and non-ADRC investigators. Aim 2: Assess, track and validate biofluid and tissue biomarkers of AD. We will use standardized ELISA-based assays for Abeta1-40, Abeta1-42, t-tau and p- tau in CSF in existing and future biofluid samples from Yale ADRC Biorepository, as well as utilize state-of-the- art targeted mass spectrometric assays to analyze selected biomarkers in biofluid and brain tissue from the Yale ADRC Biorepository and other ADRC-affiliated research projects. Aim 3: Assess, track and validate systems-level biomarkers based on high-dimensional omics data. We will assess DNA methylation (DNAm) in biofluids from the Yale ADRC Biorepository and other ADRC-affiliated research projects, and use it to calculate both validated and novel biomarker measures of epigenetic age and AD heterogeneity. Working with the DMSC, we will use systems biology approaches to integrate the DNAm and proteomic data with data available via the Clinical and Imaging Cores. Aim 4: Facilitate training and Outreach in AD Biomarker acquisition and use.